Metoclopramide antagonism of 5-hydroxytryptophan-induced “Wet-Dog” shake behaviour in the rat

Summary

• 1. Metoclopramide, a drug with blocking activity at peripheral neuronal receptor sites for 5-hydroxytryptamine (5-HT), was investigated as an antagonist of the ‘Wet-Dog’ shake response (WDS) to injections of 5-hydroxytryptophan (5-HTP) in rats. Its effects were compared with those of methysergide, an antagonist of 5-HT at non-neuronal receptor sites, and haloperidol, a dopamine receptor antagonist.

• 2. WDS after 5-HTP and carbidopa, an inhibitor of peripheral aromatic l-amino acid decarboxylase, correlates significantly with the increase in whole brain 5-HT concentrations measured in parallel experiments.

• 3. Metoclopramide, methysergide and haloperidol inhibited WDS. Metoclopramide, in addition, inhibited the increase in brain 5-HT, but not, apparently, by interfering with the decarboxylase enzyme.

• 4. Inhibition of the rise in brain 5-HT could not explain inhibition of WDS by metoclopramide, since metoclopramide inhibited 5-HTP-induced shaking once established and also the response to quipazine, a directly-acting agonist at central 5-HT receptors.

• 5. The mechanism of action of methysergide may involve blockade of post-synaptic receptor sites for 5-HT. Metoclopramide and haloperidol, on the other hand, cause catalepsy at doses which inhibit WDS, presumably through blockade of dopamine receptors in the CNS. The consequent inhibition of the ability of the animals to initiate movement may be the mechanism by which these compounds inhibit WDS.

• 6. Since agents with cataleptic properties, probably unconnected to brain 5-HT mechanisms, are effective antagonists of the shaking response, WDS after 5-HTP may be less useful than previously supposed as a screen for durgs interacting with 5-HT receptors in the CNS.